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Saroglitazar Deactivates the Hepatic LPS/TLR4 Signaling Pathway and Ameliorates Adipocyte Dysfunction in Rats with High-Fat Emulsion/LPS Model-Induced Non-alcoholic Steatohepatitis

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Abstract

The most epidemic liver disorder non-alcoholic steatohepatitis (NASH) is characterized by hepatic steatosis and inflammation with hepatocellular damage. Recently, it is predictable to be the extensive cause for liver transplantation. The absence of an approved therapeutic agent for NASH is the reason for investigating saroglitazar (SAR) which showed promising effects as a dual PPAR-α/γ agonist in recent studies on NASH. Here, we aimed to investigate the effect of SAR on NASH induced in rats by the administration of high-fat emulsion (HFE) and small doses of lipopolysaccharides (LPS) for 5 weeks. Rats were divided into three groups: negative control group (saline and standard rodent chow), model group (HFE(10 ml/kg/day, oral gavage) + LPS(0.5 mg/kg/week, i.p)), and SAR-treated group (HFE(10 ml/kg/day, oral gavage) + LPS(0.5 mg/kg/week, i.p.) + SAR(4 mg/kg/day, oral gavage) starting at week 3.Treatment with SAR successfully ameliorated the damaging effects of HFE with LPS, by counteracting body weight gain and biochemically by normalization of liver function parameters activity, glucose, insulin, homeostasis model of assessment (HOMA-IR) score, lipid profile levels, and histopathological examination. Significant changes in adipokine levels were perceived, resulting in a significant decline in serum leptin and tumor necrosis factor-α (TNF-α) level concurrent with adiponectin normalization. The positive effects observed for SAR on NASH are due to the downregulation of the LPS/TLR4 pathway, as indicated by the suppression of hepatic Toll-like receptor 4 (TLR4), NF-κB, TNF-α, and transforming growth factor-β1 (TGF-β1) expression. In conclusion, this work verified that SAR ameliorates NASH through deactivation of the hepatic LPS/TLR4 pathway and inhibition of adipocyte dysfunction.

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Abbreviations

NASH:

Non-alcoholic steatohepatitis

LPS:

Lipopolysaccharide

HFE:

High-fat emulsion

SAR:

Saroglitazar

ALT:

Alanine aminotransaminase

AST:

Aspartate aminotransaminase

LDL:

Low-density lipoprotein

NAFLD:

Non-alcoholic fatty liver disease

HOMA:

Homeostasis model of assessment

TLR4:

Toll-like receptor 4

TNF-α:

Tumor necrosis factor-α and

TGF-β1:

Transforming growth factor-β1

NAFLD:

Non-alcoholic fatty liver disease

HCC:

Hepatocellular carcinoma

PPARs:

Peroxisome proliferator-activator receptors

CMC:

Carboxymethyl cellulose

FFAs:

Free fatty acids

i.p:

Intraperitoneal

H&E:

Hematoxylin and eosin

LH:

Lobular hepatitis

HB:

Hepatocellular ballooning

PH:

Portal hepatitis

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Acknowledgments

This manuscript has been appreciatively scientifically edited by the Nature Research Editing Service through the Egyptian knowledge bank.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Modern University for Technology and Information, Cairo, Egypt

    Noha F. Hassan

  2. Department of Pharmacology and Toxicology, National Research Centre, Giza, Egypt

    Somaia A. Nada

  3. Department of Pathology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt

    Azza Hassan

  4. Department of Biochemistry, Faculty of Pharmacy, Modern University for Technology and Information, Al-Mokattam, Cairo, Egypt

    Mona R. El-Ansary

  5. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Cairo, Egypt

    Muhammad Y. Al-Shorbagy & Rania M. Abdelsalam

  6. School of Pharmacy, Newgiza University, Giza, Egypt

    Muhammad Y. Al-Shorbagy

Authors
  1. Noha F. Hassan
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  2. Somaia A. Nada
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  3. Azza Hassan
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  4. Mona R. El-Ansary
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  5. Muhammad Y. Al-Shorbagy
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  6. Rania M. Abdelsalam
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Corresponding author

Correspondence to Mona R. El-Ansary.

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Ethics Statement

Experimental design and animal handling procedures were approved by the Faculty of Pharmacy, Cairo University Research Ethics Committee, Cairo, Egypt: PT number (1742) and complied with the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH Publication no. 85–23, revised 1996). Every effort was made to minimize the number and suffering of animals used in this study.

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The authors declare that they have no conflicts of interest.

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Hassan, N.F., Nada, S.A., Hassan, A. et al. Saroglitazar Deactivates the Hepatic LPS/TLR4 Signaling Pathway and Ameliorates Adipocyte Dysfunction in Rats with High-Fat Emulsion/LPS Model-Induced Non-alcoholic Steatohepatitis. Inflammation 42, 1056–1070 (2019). https://doi.org/10.1007/s10753-019-00967-6

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  • DOI: https://doi.org/10.1007/s10753-019-00967-6

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